Chlorobenzene-2,4-disulphonic acid amide carboxylic acids

ABSTRACT

Pharmaceutical compositions are produced which comprise a compound of the formula:   WHEREIN: R is hydrogen or methyl; R&#39;&#39; is hydrogen or lower alkyl; R&#39;&#39;&#39;&#39; is hydrogen or lower alkyl; and N IS 0 OR 1; OR A PHARMACEUTICALLY ACCEPTABLE NON-TOXIC SALT THEREOF, IN COMBINATION WITH A PHARMACEUTICALLY ACCEPTABLE INERT DILUENT OR CARRIER. These compositions are useful for their saluretic effect and are useful in treating edema and hypertension.

United States Patent Horstmann et al.

Assignee: Bayer Aktiengesellschaft, Germany Filed: Jan. 11, 1974 Appl. No.: 432,744

Related US. Application Data Division of Ser. No. 62,639, Aug. 10, 1970, which is a division of Ser. No. 829,123, May 29, 1969, which is a division of Ser. No. 643,822, June 6, I967, Pat. No. 3,499,005.

Foreign Application Priority Data June 16, 1966 Germany 49487l2 US. Cl. 260/519 Int. Cl. C07c 143/40 Field of Search 260/519 References Cited UNITED STATES PATENTS 3/l97l Liebenow 260/519 Primary Examiner-Anton H. Sutto Assistant Examiner-L. A. Thaxton [5 7] ABSTRACT Pharmaceutical compositions are produced which comprise a compound of the formula:

[ July 29, 1975 (c11 T R. I u

I H NO S SO -N-Cli (III) CH R l COOH 11 N0 8 50 l\ CH OH wherein:

R is hydrogen or methyl;

R is hydrogen or lower alkyl;

R is hydrogen or lower alkyl; and

n is 0 or I;

or a pharmaceutically acceptable non-toxic salt thereof, in combination with a pharmaceutically acceptable inert diluent or carrier. These compositions are useful for their sa-luretic effect and are useful in treating edema and-hypertension.

1 Claim, N0 Drawings wherein R is hydrogen or methyl, R is hydrogen or lower alkyl, R" is hydrogen or lower alkyl and n O or 1, and their pharmaceutically acceptable non-toxic salts. These compounds have been found to be useful saluretics and have been found to possess a much greater diuretic-saluretic effect than known compounds and a much more advantageous KAVK quotient. 2,4-disulphamyl-chlorobenzenes of the formula:

H NO S v SO M-I are known to have salt-eliminating effects [cf. Jakob, Dtsch.Xed. Wschr. 85, 814 (1960)]. It is also known in the art that certain derivatives of 2,4-disulphamylchlorobenzene, in which the sulphamyl radical in the p-position to the chlorine atom is monoor disubstituted, are superior to the unsubstituted compound in salt-elminating or saluretic effects (of. Belgian Pat. No. 598.722; German Pat. Nos. 1,096,897 and 1,111,618). On comparison with the effectiveness of commercial diuretics of the sulphonamide series, such as hydrochlorothiazide [U.S. Pat. No. 2,809,194; Experientia 14, 458 (1958)], the effect of the benzene-mdisulphonamides referred to above must be regarded as poor, and, according to the present state of the art, have only limited clinical interest in applicability.

All of the above compounds have in common the fact that besides the desired elimination of Na and C1 ions, K ions are simultaneously eliminated to a greater or lesser degree. This results in a very serious contra- (CHQERII 2.. wherein R is-hydrogen methyl. is hydrogen or lower alkyl, R is hydrogen or lower alkyl and h is 0 or 1. have a much greater diuretic saluretic effect an d 'a' much more advantageous Na/K" quotientt'han presently known diuretic-salu retic compounds. The disulphonamides (lll) ma y be obtained by a. reacting -4-chloro-3-sulphonaniido-beniene sulphochloride of the formula:'

with amines and/or their salts of the formula:

(n) i i i i '8 H NO S S0 with an aminoalkyl-hydroxy-carboxylic acid, aminoalkylhydroxy-carboxylic acid ester or salt of the formula:

R RI RI! HN-CH CCJY closing the lactone ring-by subsequent heating .with hydrolysing age'nts,'if desired after. acidificatiomand heating; i

with oxidizing agents; or

d. converting the salts of hydroxycarboxylic acids of the formula:

H NO S (VII) in an alkaline medium into the cyclic form (1) by acidification, such as with hydrochloric acid, and, if desired, by heating, wherein R is hydrogen or methyl, R is hydrogen or lower alkyl, R" is hydrogen or lower alkyl, X is an OH group or its reactive esters, such as the tosyloxy group or halogen, Y is an OH group, O-lower alkyl or OMe group wherein Me is ia'n alkali metal or alkaline earth metal and his or 1.

According to process (a). the amines of the formula II are preferably used in the form of their salts, such as the hydrochlorides or acetates and are liberated in the presence'of sulphoehloride (l) by acid-binding agents, The aminoalkyl-lactonesof the formula ll can also be replaced with-the aminoalkyl-hydroxy acids (IV) from which they are derived and which may be in equilibrium in aqueous media according, to the followi ng:

' chromic acid, nitric acid, ruthenium dioxide, manganese dioxide, oxygen or air, at an elevated temperature and increased pressure in the presence of known catalysts.

The dis ulphonamides of the formula [I] obtained according to the processes disclosed herein may be present in equilibrium with hydroxycarboxylic acid (Vll) from,which they are derived:

In an alkaline medium, the salts of hydroxycarboxylic acids (Vll) may be present to a considerable extent. These compounds are converted into the cyclic form of the disulphonamides (Ill) by acidification, such as with hydrochloric acid, and, if desired, by heating.

With non-toxic bases, disulphonamides (Ill) ,form

' salts which are derived either from (III) or (V) depending upon whether one or two equivalents of a correspo nding base have been used. I

On comparison with known diuretics and saluretics, the compounds of the present invention not only exhibit a higher activity and a substantially improved Nal/K quotient, but they are also suitable for parenteral administration to humans and animals by virtue of the fact that, in contrast to many diuretics-saluretics, they are soluble in the form of their monosalts at an almost neutral pH. No stabiliziers are required for the preparation of the aqueous solution to be used for parenteral administration.

The products according to the present invention are also useful for sweeping out edema of various genuses as well as for the treatment of hypertension. In the treatment of edema, preparations containing the disulphonamides of the present invention are administered in a dosage in the range of from 20 to mg per day. When used in the treatment of hypertension, which normally requires treatment for a prolonged period of time, a dosage in the range of 10 to 30 mg per day is used.

The compounds of the present invention may be mixed with pharmaceutically inert carriers, such as talc, lactose, starch, ethylcellulose, agarpectin, stearic acid, magnesium stearate, sodiumbicarbonate or gelatin.

For parenteral application salts with non-toxic bases of the open ring hydroxycarboxylic acid are used.

These salts enable the preparation of stable aqueous EXAMPLE 1 v v 190 grams" (0.5 mole) "chlorobenzene-'2,4- disulphonic acid amide-( 2 a-(u-methyl tetrahydrofurfuryl]-N methylamide-(4) "are dissolved in a-solution of 40 g Na'OH (1 mole) in 1 litre of water. 126 grams potassium permanganate are added, the mixture isstirred at 50C for hours, filtered off from pyrolusite, the filtrate. is buffered with an ammonium chloride solution and the starting material filtered off. After subsequent acidification with dilute hydrochloric acid, chlorobenzene-2,4-disulphonic acid amide-(2)- [a-(a-methyLoU-oxo)-tetrahydrofurfuryl]-N- methylamide-(4) is precipitated and crystallizes completely in the course of several hours. M.p. 153 to 156C (alcohol), yield 1 18 g. A further g of crude lactone can be isolatedfrom the mother liquor. The total yield, referred to the reacted starting material, amounts to 81%.

EXAMPLE 2 Levo-rotatory chlorobenzene-Z,4-disulphonic acid amide-( 2 a-( a-methyl-a '-oxo )-tetrahydrofurfuryl N-methylamide-(4):

According to the method described in Example l, 19 g levor-rotatory chlorobenzene-2,4-disulphonic acid- (2 a-( a-methyl )-tetrahydrofurfuryl -N- methylamide-(4) (m.p. 145 to 146C, [011 17.l (2.0% in methanol) are dissolved in 100 ml of water and 4 g sodium hydroxide and oxidized with 12.5 g potassium permanganate. Yield 87% of theory, m.p. 168 to 170C, 1518 1546 l43s l laso 1365 The starting material is obtained in the following manner:

(dl)-2-methyl-a-aminomethyl-tetrahydrofuran is resolved with (d)()-tartaric acid into dextro-rotatory a-methyl-a-aminomethyl-tetrahydrofuran, b.p. 74 to 78C/50 mm Hg, [011 +6.65 (2.6% in chloroform); hydrochloride mp. 196C, [04 ll.33 (1.5% in methanol), and this is reacted with 4-chloro-3- sulphonamido-benzene sulphochloride to give the levorotatory chlorobenzene-Z,4-disulphonic acid amide- (2)-[a-(a-methyl)-tetrahydrofurfuryl]-N- methylamide-(4).

EXAMPLE 3 Dextro-rotatory chlorobenzene-2,4-disulphonic acid amide-(2)[a-(a-methyl-a'-oxo)-tetrahydrofurfuryl]- N-methylamide-(4):

The product which is obtained in analogy with Example 2 in a yield of 82% by oxidation of 19 g of dextrorotatory chlorobenzene-Z,4-disulphonic acid amide- (2)-[a-(a-methyl)-tetrahydrofurfuryl]-N- methylamide-(4) with 12.5 g potassium permanganate in 100 ml of water and 4 g NaOl-l, has the following constants:

6 .M.p.-. 168 -to -.l {10C, 1 rotation-tvalues; measured. in methanol own-2.01221; Balm :l-5.0; [01151463 +5.7;

. t 143 .[ahm

Starting materialz--levo-rotat0ry 'a-methyl-a-methylaminom'e'thyl-tetrahydrofuran,rb.pi 7Qto 74C/45= mm Hg, [011 6.75.. l.,6% in chloroform); hydrochloride 'rn.p. -l 96C, (a1 l-:1 0.9 (2.06%in methanol dextro-rotatory chlorobenzene-2.4 dis'ulphonic acid mcthylamidc-M), m.p. l-45 to 146 C. ['d'l +l.7.55 (2.02% in methanol). p J v EXAMPLE 4 To a solution of y-hydroxy-y-aminomethyl v aleiianic acid ethyl ester acetate, which was obtained :byhydrogenating 34.2 g 'y-hydroxy-y-cyanofvalerianicfacid methyl ester in glacial acetic acid with"a' Pt-catalyst. in 40 ml acetone and 40 ml of water-there'is-simultaneously added dropwise at 20C with vigorous centrifuging a solution of 42.75 g 4-chloro-3-sulphonamidobenzene sulphochloride in rm acetone and a solution of 31.5 g sodium carbonate in 50 ml of water. The mixture is stirred overnight, filtered off from inorganic components, concentrated by evaporation in a vacuum, the residue is taken up withwater/dilutje hydrochloric acid and the organic componeri't'sare extracted with a mixture of ether/ethyl acetate. 'Aftercvap'o'rati'on of the organic phase there remain 10 g of an oil which completely crystallizes after brief heating with dilute hydrochloric acid to give chlorobenzene-2,4- disulphonic acid amide-(2)-[a-(afmeth'yl av-oxo)- tetrahydrofurfuryll-amide-(4), m.p. 188 to l89.5C

(alcohol/water). l l

EXAMPLE 5 According to the method described in Example 4 it is also possible to start from a-aminomethyl-a-methylbutyrolactone acetate which is obtained by catalytic hydrogenation of a-cyano-a-methyl-butyrolactone in glacial acetic acid by means of a Pt-catalyst. and to react this with 4-chloro-3-sulphonamido-benzene sulphochloride in acetone in the presence ofa sodium carbonate solution. After appropriate working up there is obtained chlorobenzene-Z,4-disulphonic acid amide- (2)-[a-(a-methyl-a-oxo)-tetrahydrofurfuryl]-amide- (4), mp. 188 to l89.5C.

EXAMPLE 6 A solution of 'y-hydroxy-y-methylaminomethylvalerianic acid-lactone hydrochloride is reacted according to the method described in Example 2, with 4- chloro-3-sulphonamido-benzene sulphochloride in acetone in the presence of water. After appropriate working up, there is obtained chlorobenzene-2,4- disulphonic acid amide-(2)-[a-(a-methyl-a'-oxo)- tetrahydrofurfuryll-N-methylamide-(4) of m.p. 153 to 156C in a yield of 22%.

The y-hydroxy-y-methylaminomethyl-valerianic acid-lactone hydrochloride is obtained in the following manner:

2/10 mole y-hydroxy-y-cyano-valerianic acid methyl ester are hydrogenated in glacial acetic acid with a Ptcatalyst. The mixture is evaporated in a vacuum, the residue dissolved in a little alcohol, 26.5 g benzaldehyde are added and then 6.5 g NaOH dissolved in 100 m1 of alcohol are slowly added dropwise at 20C. After the addition of benzene, the mixture is stirred at 50C for 10minutes, evaporated in a vacuum, taken up with a 200 ml of benzene and, after the addition of2-2- g dimethyl sulphate. heated at 90C for a good minutes. 'The reaction product is decomposed with dilute hydro chloric acid; the precipitated benzaldehyde is extracted with ether and after evaporation there is obtained crude y-hydroxy-y-methylamino-methyl-valerianic "acid-lacto'ne hydrochloride which is reacted, without previous purification. with 42 g 4-chloro-3- sulphonamido-benzene sulphochloride.

' EXAMPLE 7 In analogy with Example 1. there were obtained: Chlorobenzene-Z,4-disulphonic acid amide-(ZHa- (a'-oxo-tetrahydrofurfuryl]-N-methylamide-(4) of the v formula: c1

- l 11 ba no s SO -NCH o m.p. l 38-140C, yield 38% of theory;

Chlorobenzene-2,4-disulphonic acid m.p. 142 145c. yield 38% of theory.

amide-(2)- -[a(a fl dimethyl-a -oxo)-methyl-tetrahydropyranyl]- N rnethylamide(4) of the formula:

EXAMPLE 8 50 g of chlorobenzene-Z,4-disulphonic acid amide- (2-[a-( a-methyl-a-oxo )-tetrahydrofurfuryl ]-N- methylamide-(4). 7 g of sodiumbicarbonate and 2.5 g of magnesium stearate are ground and filled with gelatin capsules each containing 0.05 g.

EXAMPLE 9 R! RU SC -N-CH COOH H NO S 2 2 0H wherein:

R is hydrogen or methyl: R is hydrogen or lower alkyl; R is hydrogen or lower alkyl. n is 0 or 1; and pharmaceutieally acceptable non-toxic salts thereof.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT N0. 3,897,488

DATED 1 July 30, 1975 INVENTOR(S) HARALD HORSTMANN, et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Related U. S Application Data should read:

-- This is a divisional of our copending application Serial No. 62,639 filed August 10, 1970, which is a divisional of our application Serial No. 643, 822 filed June 6, 1967, now

Patent No 3,499, 005

Column 1, lines 3-7, should read:

- This is a divisional of our copending application Serial No. 62, 639 filed August 10, 1970, which is a divisional of our application Serial No. 643, 822 filed June 6, 1967, now

Patent No. 3,499,005.

Signcd and Sealed this sixteenth D 8) 0f December 1 9 75 [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner ofParenls and Trademarks 

1. A COMPOUND OF THE FORMULA: 